Developmental Biology - Spinal Cord Injury|
Target For Restoring Spinal Cord Injury
Indiana Universary identifies potential target for restoring movement after spinal cord injury...
Researchers at Indiana University School of Medicine working on animal models, made several novel discoveries in the field of Spinal Cord Injuries (SCI). The team was led by Xiao-Ming Xu PhD. Xu has been trying to re-activate movement following spinal cord injury at the ninth thoracic junction, where nerve fibers from the brain enter the spinal cord.
Instead of focusing on the injury site, researcher Qi Han and his colleagues manipulated the spared lumbar circuits below the injury to improve recovery from spinal cord injury or SCI.
The team observed how modifying the interrupted lumbar motor circuits using neurotrophic therapy improved locomotor performance. Their findings are published in the December 20 issue of Nature Communications.
"There are no definitive treatments yet for SCI patients. However, hope for restoring motor function continues to rise and for good reason. We find despite there being no direct damage from thoracic SCI, the lumbar circuit undergoes profound neurodegeneration, which we see as a promising therapeutic target for neuroprotection."
Qi Han PhD, Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
SCI disrupted pathways at injury sites affects lower motor neurons (MNs) by causing dendrites to shrink or atrophy below the injury site. This can lead to diminished movement and/or locomotor function lower down the spine. Previously, the research team was able to improve locomotor recovery by reducing MN dendritic atrophy by introducing Neurotrophin-3 (NT-3) onto lower lumbar motor neurons.
NT-3 is known as a trophic factor, contributing to neuronal survival and growth. These latest findings extend its role to reorganizing the propriospinal-motor neuron circuit, and improving locomotor function after spinal cord injury.
Researchers determined how creating injury in mice at the ninth thoracic level stops corticospinal tracking and rubrospinal tract projections all the way down the spinal cord. However, some neural transmissions can be reinforced using NT-3 therapy. These neurons are made up of a collection of nerve fibers called the descending propriospinal pathway. This pathway reconnected the lumbar spinal cord with locomotor NT-3-mediated recovery even after injury.
The research suggests NT-3 supports motor neuron recovery by promoting dendrite regrowth.
"Modulating propriospinal-MN circuitry with NT-3 gene therapy could be an attractive strategy to enable functional recovery after SCI," says Xu. He hopes their research findings lay the groundwork for more NT-3 therapy to help patients with SCI in the near future.
Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.
Qi Han, Josue D. Ordaz, Nai-Kui Liu, Zoe Richardson, Wei Wu, Yongzhi Xia, Wenrui Qu, Ying Wang, Heqiao Dai, Yi Ping Zhang, Christopher B. Shields, George M. Smith and Xiao-Ming Xu.
This work was supported in part by NIH 1R01 100531, 1R01 NS103481, Merit Review Award I01 BX002356, I01 BX003705, I01 RX002687 from the U.S. Department of Veterans Affairs, Indiana State Department of Health (ISDH, Grant# 19919), Mari Hulman George Endowment Funds (X-M.X), DOD grant and Shriners (GMS). Additional thanks to Baylen Ravenscraft for his editing suggestions.
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(RIGHT) Rat spinal cord injury caused by injection of tPA stroke drug shows neural progenitor axons bright in color. (LEFT) Spinal axons pre-conditoned with protective NT-3 reflect measurable increase in propriospinal pathway transmissions following injury.